CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis
CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis
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CCR2 和 CCR5 介导的巨噬细胞浸润导致抗体诱导的狼疮肾炎中肾小球毛细血管内细胞增多
DOI：
10.1093/rheumatology/keab825
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Kawano M.
中科院分区：
文献类型：
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作者：
Zoshima T;Baba T;Tanabe Y;Ishida Y;Nakatani K;Nagata M;Mukaida N;Kawano M.
目的ln包括多种肾小球病变，包括毛细血管内高细胞伴巨噬细胞浸润。在这项研究中，我们旨在阐明巨噬细胞趋化因子受体在这些肾小球病变发病机制中的作用。方法将smrl /lpr小鼠来源的产生IgG3抗体的单克隆杂交瘤2B11.3和B1腹腔注射BALB/c小鼠[野生型（WT）]，分别诱导毛细血管内细胞增多和丝环病变。采用实时荧光定量PCR和IF分析趋化因子及趋化因子受体的表达。在趋化因子受体缺陷小鼠和选择性CCR5拮抗剂maraviroc的实验中，研究人员对趋化因子受体在这些病变中的作用进行了评估。结果2b11.3引起肾小球毛细血管内高细胞化，肾小球cd68阳性巨噬细胞数量显著增加。此外，与注射B1相比，CCL2、CCL3、CCR2、CCR5和CX3CR1在肾皮质的表达增强，引起丝环病变。在2b11.3诱导的肾小球病变中，CD68阳性的肾小球巨噬细胞表达CCL2、CCL3、CCR2、CCR5和CX3CR1，肾小球内皮细胞表达CCL2、CCL3、CX3CL1和CCR2。当注射2B11.3、CCR2 - /和CCR5 - / -，而不注射CX3CR1 - / -时，小鼠毛细血管内高细胞性减少，肾小球巨噬细胞浸润减弱，血清尿素氮水平提高。只有CCR2 - / -小鼠出现丝环病变。B1注射在这些趋化因子受体缺乏的小鼠中引起的钢丝环病变程度与WT相似。马拉韦洛克治疗减少了2b11.3诱导的毛细血管内高细胞性，提高了血清尿素氮水平。结论ccr2和CCR5调节肾小球巨噬细胞浸润，参与肾小球毛细血管内高细胞的形成。抑制CCR5可作为一种不诱导丝环病变的毛细血管内高细胞性的特异性治疗方法。
ObjectivesLN comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions.MethodsMRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice [wild type (WT)] to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analysed by quantitative real-time PCR and IF. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc.Results2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5 and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68 -positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5 and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1 and CCR2. When 2B11.3 was injected, CCR2–/–and CCR5–/–, but not CX3CR1–/–, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration and improved serum blood urea nitrogen levels. Only CCR2–/–mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum blood urea nitrogen levels.ConclusionCCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in LN. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.